ABSTRACT Diabetes mellitus remains a leading cause of blindness world-wide and epidemiological data from the World Health Organization reveal over 422 million adults live with diabetes and the rate of disease onset continues to rise. According to the National Eye Institute 10.2 million US adults 40 years and older have diabetes mellitus, and 8.2% with vision threatening retinopathy. Macular edema remains closely linked to loss of vision and current therapies focus on mechanisms to prevent cytokine driven changes in vascular permeability that promote edema. Our previous research has fundamentally contributed to understanding the molecular mechanisms that lead to vascular endothelial growth factor (VEGF) induced retinal vessel permeability. The development of effective anti-VEGF therapies has been a welcome addition for the treatment of diabetic retinopathy, but this approach remains insufficient and new therapies are needed. In the current application we now focus on understanding the process of blood-retinal barrier regeneration. Research has identified a required role for norrin in formation of the blood-retinal barrier. Here, we explore the exciting potential for norrin to restore vascular barrier properties after VEGF-induced injury. The studies promise to shed new light on how these two critical cytokines interact to control retinal vessel barrier properties. Further, preliminary data reveal completely novel interactions of the norrin signaling molecule, disheveled (DVL), binding directly to tight junction proteins. The role of these protein interactions on norrin signaling and tight junction biology will be elucidated at a molecular level in order to understand the mechanisms of norrin action on barrier restoration. We expect this proposal will provide novel information on regulation of the blood-retinal barrier in health and in diabetes and will provide a framework from which to develop potential new therapeutic options to treat macular edema.